Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2

Yokosuka, Tadashi; Takamatsu, Masako; Kobayashi-Imanishi, Wakana; Hashimoto-Tane, Akiko; Azuma, Miyuki; Saito, Takashi

doi:10.1084/jem.20112741

Cited by 942 publications

(743 citation statements)

References 51 publications

Supporting

Mentioning

680

Contrasting

Unclassified

Order By: Relevance

“…2D). Since PD-1 is known to mediate its inhibitory function in T cells by increasing TcR activation threshold through the regulation of early TcR signaling [23], our data supported the notion that miR-155 expression in adaptively tolerant T cells was conditioned directly by TcR signals. This assumption was verified by stimulating in vitro purified adaptively tolerant T cells in the presence of varying concentrations of immobilized PD-L1-Ig.…”

Section: Mir-155 Is Strongly Expressed By Adaptively Tolerant Cd4 + Tsupporting

confidence: 81%

Micro‐RNA‐155‐mediated control of heme oxygenase 1 (HO‐1) is required for restoring adaptively tolerant CD4⁺ T‐cell function in rodents

et al. 2015

View full text Add to dashboard Cite

T cells chronically stimulated by a persistent antigen often become dysfunctional and lose effector functions and proliferative capacity. To identify the importance of micro-RNA-155 (miR-155) in this phenomenon, we analyzed mouse miR-155-deficient CD4 + T cells in a model where the chronic exposure to a systemic antigen led to T-cell functional unresponsiveness. We found that miR-155 was required for restoring function of T cells after programmed death receptor 1 blockade. Heme oxygenase 1 (HO-1) was identified as a specific target of miR-155 and inhibition of HO-1 activity restored the expansion and tissue migration capacity of miR-155 −/− CD4 + T cells. Moreover, miR-155-mediated control of HO-1 expression in CD4 + T cells was shown to sustain in vivo antigen-specific expansion and IL-2 production. Thus, our data identify HO-1 regulation as a mechanism by which miR-155 promotes T-cell-driven inflammation.Keywords: Adaptive tolerance r Heme oxygenase 1 (HO-1) r Immunoregulation r Micro-RNA r Th1Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionT lymphocytes are a crucial part of the immune system and are a major cell type involved in the adaptive immune response. Usually, T cells expand rapidly in response to antigenic stimulation, and then, as a result of antigen clearance, they die by apoptosis. However, in situations of chronic antigenic exposure, such as those observed in cancer, chronic infections, or autoimmunity, antigen-specific T cells may persist for extended periods of time and these conditions are often associated with T-cell Correspondence: Dr. Michel Y. Braun e-mail: mbraun@ulb.ac.be dysfunction, such as decreased cytokine expression and effector function. Recent experimental evidence indicates that this unresponsive state is maintained by the inhibition of signaling events, particularly downstream proximal signals of the T-cell receptor, that in turn promotes T-cell dysfunction [1][2][3][4]. Since the attenuation of T-cell effector functions by the programmed death receptor 1 (PD-1) pathway has been demonstrated in various chronic infectious diseases and cancer and in the control of autoimmune T cells, the modulation of this inhibitory pathway is considered a promising means to control the function of T cells or enhance immune responses in patients.Micro-RNAs (miRNAs) are small genome-encoded RNAs that regulate gene expression by targeting complementary messenger RNAs (mRNAs) and block their translation [5,6]. The first C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 830Jinyu Zhang et al. Eur. J. Immunol. 2015. 45: 829-842 evidence for the involvement of miRNAs in regulating T-cell differentiation and function came from the observation that the specific deletion of the endoribonuclease DICER, a RNaseIII-like enzyme required for generating miRNAs, in the CD4 + T-cell lineage resulted in impaired T-cell development and aberrant Th1-cell differentiation and cytokine production [7]. Among miRNAs the mo...

show abstract

Section: Mir-155 Is Strongly Expressed By Adaptively Tolerant Cd4 + Tsupporting

confidence: 81%

Micro‐RNA‐155‐mediated control of heme oxygenase 1 (HO‐1) is required for restoring adaptively tolerant CD4⁺ T‐cell function in rodents

et al. 2015

View full text Add to dashboard Cite

show abstract

“…However, recent studies using single-cell imaging demonstrate that on ligation with its ligand, PD-1 clusters with the TCR and transiently associates with the phosphatase SHP2, resulting in dephosphorylation of signaling molecules and direct inhibition of T-cell activation (38). Importantly, this PD-1-mediated inhibitory mechanism was apparent in T cells activated in vitro and PD-1 hi T cells generated in vivo (38). We hypothesize that transient expression of PD-1 induced by antigen exposure in a vaccination setting may be an immunoregulatory mechanism contributing to contraction of the M72-specific effector CD4 T-cell response.…”

Section: Discussionmentioning

confidence: 99%

Induction and Regulation of T-Cell Immunity by the Novel Tuberculosis Vaccine M72/AS01 in South African Adults

Day

Tameris

Mansoor

et al. 2013

Am J Respir Crit Care Med

108

View full text Add to dashboard Cite

Rationale: Tuberculosis (TB) is a major cause of morbidity and mortality worldwide, thus there is an urgent need for novel TB vaccines. Objectives: We investigated a novel TB vaccine candidate, M72/ AS01, in a phase IIa trial of bacille Calmette-Gué rin-vaccinated, HIV-uninfected, and Mycobacterium tuberculosis (Mtb)-infected and -uninfected adults in South Africa. Methods: Two doses of M72/AS01 were administered to healthy adults, with and without latent Mtb infection. Participants were monitored for 7 months after the first dose; cytokine production profiles, cell cycling, and regulatory phenotypes of vaccine-induced T cells were measured by flow cytometry. Measurements and Main Results: The vaccine had a clinically acceptable safety profile, and induced robust, long-lived M72-specific T-cell and antibody responses. M72-specific CD4 T cells produced multiple combinations of Th1 cytokines. Analysis of T-cell Ki67 expression showed that most vaccination-induced T cells did not express Th1 cytokines or IL-17; these cytokine-negative Ki67 1 T cells included subsets of CD4 T cells with regulatory phenotypes. PD-1, a negative regulator of activated T cells, was transiently expressed on M72-specific CD4 T cells after vaccination. Specific T-cell subsets were present at significantly higher frequencies after vaccination of Mtb-infected versus -uninfected participants. Conclusions: M72/AS01 is clinically well tolerated in Mtb-infected and -uninfected adults, induces high frequencies of multifunctional T cells, and boosts distinct T-cell responses primed by natural Mtb infection. Moreover, these results provide important novel insights into how this immunity may be appropriately regulated after novel TB vaccination of Mtb-infected and -uninfected individuals. Clinical trial registered with www.clinicaltrials.gov (NCT 00600782).Keywords: tuberculosis; vaccine; T cell; cytokine; proliferation Tuberculosis (TB) remains a major cause of morbidity and mortality, with approximately 9 million new cases and 1.5 million deaths worldwide each year (1). Bacille Calmette-Guérin (BCG) provides protection against miliary TB and TB meningitis in children (2); however, BCG provides variable efficacy against pulmonary TB in adults (3), the most common clinical manifestation of the disease. Mycobacterium tuberculosis (Mtb) is transmitted primarily by adults; therefore novel, effective TB vaccines are urgently needed to target this population, and thereby reduce the burden of TB disease worldwide.Phase I and II clinical trials of several novel candidate TB vaccines have either been completed or are currently ongoing (4). These vaccines include the candidate recombinant fusion protein vaccine M72, formulated with GlaxoSmithKline Vaccines Approximately one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb), and despite the widespread use of the bacille Calmette-Guérin vaccine, tuberculosis (TB) remains a major cause of morbidity and mortality. There is an urgent need to develop novel TB vaccines that are safe,...

show abstract

“…Several studies documented the usage of costimulatory molecule as an antitumor immunotherapy to trigger and enhance strong T-cell response against tumor by different combination approaches (Xiao et al, 2007). Programmed death-1(PD-1) is the type I transmembrane immunoinhibitory receptor expressed on activated T and B cells, consist of single extracellular Ig-like variable (IgV) domain and an intercellular part contains an immunoreceptor tyrosine-based inhibitory motif (Xu et al, 2006), which delivers negative signals upon ligation to its two ligands B7-H1 and B7-DC (Youngnak et al, 2003;Yokosuka et al, 2012). PD-L1 a recently identified coinhibitory molecule belonging to the B7 family molecules (Lee et al, 2005), it is expressed in cells of lymphocyte lineage and is also found in the tissues of various organs, including non-lymphoid organs, such as the heart, lung, placenta, kidney, and liver and several tumor cell lines (Freeman et al, 2000;Paterson et al, 2011), and it can promote the apoptosis of tumor specific CTL and leads to immune evasion of tumor (Dong et al, 2003;Wong et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Reconstructed Adeno-Associated Virus with the Extracellular Domain of Murine PD-1 Induces Antitumor Immunity

Elhag¹,

Hu²,

Zhang³

et al. 2012

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2

Abstract: After encounter with its ligand, PD-1 translocates into TCR microclusters, where it transiently recruits SHP2 and suppresses phosphorylation of TCR signaling components and TCR-driven stop signals.

Cited by 942 publications

References 51 publications

Micro‐RNA‐155‐mediated control of heme oxygenase 1 (HO‐1) is required for restoring adaptively tolerant CD4⁺ T‐cell function in rodents

Micro‐RNA‐155‐mediated control of heme oxygenase 1 (HO‐1) is required for restoring adaptively tolerant CD4⁺ T‐cell function in rodents

Induction and Regulation of T-Cell Immunity by the Novel Tuberculosis Vaccine M72/AS01 in South African Adults

Reconstructed Adeno-Associated Virus with the Extracellular Domain of Murine PD-1 Induces Antitumor Immunity

Contact Info

Product

Resources

About

Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2

Abstract: After encounter with its ligand, PD-1 translocates into TCR microclusters, where it transiently recruits SHP2 and suppresses phosphorylation of TCR signaling components and TCR-driven stop signals.

Cited by 942 publications

References 51 publications

Micro‐RNA‐155‐mediated control of heme oxygenase 1 (HO‐1) is required for restoring adaptively tolerant CD4+ T‐cell function in rodents

Micro‐RNA‐155‐mediated control of heme oxygenase 1 (HO‐1) is required for restoring adaptively tolerant CD4+ T‐cell function in rodents

Induction and Regulation of T-Cell Immunity by the Novel Tuberculosis Vaccine M72/AS01 in South African Adults

Reconstructed Adeno-Associated Virus with the Extracellular Domain of Murine PD-1 Induces Antitumor Immunity

Contact Info

Product

Resources

About

Micro‐RNA‐155‐mediated control of heme oxygenase 1 (HO‐1) is required for restoring adaptively tolerant CD4⁺ T‐cell function in rodents

Micro‐RNA‐155‐mediated control of heme oxygenase 1 (HO‐1) is required for restoring adaptively tolerant CD4⁺ T‐cell function in rodents